CXCR6 and CXCL16 in liver disease

Abstract

BackgroundChemokines are small molecules that act through G-protein coupled receptors to mediate primarily lymphocyte migration. CXCL16, which interacts with only one receptor (CXCR6), can mediate lymphocyte recruitment and has been implicated in various disease conditions. Steatohepatitis, caused by metabolic syndrome or alcohol misuse, is the commonest cause of liver disease in the UK. We investigated the role of CXCL16 and CXCR6 in the development of steatohepatitis. MethodsExpression of CXCL16 in whole liver and isolated cells was investigated with real-time PCR and immunohistochemistry. Serum and supernatant concentrations of soluble CXCL16 were measured with ELISA. Expression of CXCR6 on lymphocytes was investigated with flow cytometry. Lymphocyte adhesion was assessed with freshly isolated lymphocytes from liver or peripheral blood flowed over confluent layer of isolated human hepatic sinusoidal endothelium (HSEC). FindingsWhole liver expression of CXCL16 was increased relative to normal liver in fatty liver disease with increasing expression seen with increasing steatohepatitis and fibrosis. Immunohistochemistry showed CXCL16 expressed throughout regenerative nodules in both alcoholic and non-alcoholic liver disease. Isolated HSEC, biliary epithelial cells, and hepatoma cell lines increased expression of CXCL16 and released soluble CXCR6 in response to pro-inflammatory cytokines, particularly the combination of tumour necrosis factor α and interferon γ. Peripheral blood lymphocyte CXCR6 expression was confined to CD4 cells; however in the liver CD8+ cells and CD56+ cells more commonly expressed CXCR6. Inhibition of CXCR6 or CXCL16 inhibited transmigration of lymphocytes across HSEC. InterpretationCXCL16 is expressed in diseased liver where it has a role in the transmigration of lymphocytes across endothelium. This may represent a new therapeutic target in liver disease. FundingUK Medical Research Council.